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Anesthetic effects in mitochondrial disease

线粒体疾病中的麻醉作用

基本信息

批准号：
7417881
负责人：
PHILIP G MORGAN
金额：
$ 19.29万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7417881
关键词：
Affect Age Anesthesia procedures Anesthetics Animal Model Biopsy Caenorhabditis elegans Cardiac Cells Child Child Care Clinical Complex Coupled Data Defect Depressed mood Diagnosis Disease Dose Electron Transport Employee Strikes Encephalopathies Endocrine System Diseases Energy-Generating Resources Gases General Anesthesia General anesthetic drugs Generations Histocompatibility Testing Human Hypersensitivity Incidence Investigation Knowledge Laboratories Lead Link Metabolism Mitochondria Mitochondrial Diseases Mitochondrial Electron Transport Complex I Mitochondrial Proteins Molecular Monitor Muscle Mutation Myopathy NADH Nematoda Neurologic Neurons Operating Rooms Operative Surgical Procedures Outcome Oxidative Phosphorylation Oxygen Patient Care Patients Pharmacogenetics Physicians Physiological Publishing Range Relative (related person)Reporting Research Personnel Respiration Respiratory Chain Risk Safety Stress Techniques Thinking Tissues Translational Research base clinical phenotype improved indexing nervous system disorder patient safety programs response sevoflurane success translational approach translational study

项目摘要

DESCRIPTION (provided by applicant): Data from our laboratory shows that specific mitochondria! mutations can change the response of an animal model to volatile anesthetics. The mutation gas-1 alters a single subunit of complex I of the mitochondrial electron transport chain. This mutation makes the nematode C. elegans very hypersensitive to volatile anesthetics. We have now shown that complex I activity correlates with anesthetic sensitivity in C. elegans across a wide range of activities. In children with mitochondrial diseases, published reports have cited severe, unexplained complications occurring during and following anesthetic exposure. We have now anesthetized 35 children who have come to the operating room for diagnosis or treatment of putative mitochondrial disease. Given reports of bad outcomes in children with mitochondrial cytopathies following anesthetic exposure, we induced these children very slowly with a single volatile anesthetic. Seven of these children were very hypersensitive to sevoflurane. All 7 of the hypersensitive children had defects consistent with decreased function of mitochondrial complex I. This is the first report of a specific physiologic defect that can profoundly change anesthetic sensitivity in humans. We hypothesize that children with mitochondrial defects specific to complex I are hypersensitive to volatile anesthetics; they may be at greater risk for adverse outcomes based on this hypersensitivity. The specific aims of this study are to: 1) prospectively determine the sensitivity of children with mitochondrial defects to the volatile anesthetic sevoflurane, and correlate sensitivity with the underlying mitochondrial disorder; 2) establish the relative safety of sevoflurane for use in children with mitochondrial disease. These translational studies have important implications for patient safety as well as for the understanding the mechanism of action of volatile anesthetics. .

描述（由申请人提供）：我们实验室的数据显示，特定的线粒体！突变可以改变动物模型对挥发性麻醉剂的反应。突变气体-1改变线粒体电子传递链复合物I的单个亚基。这种突变使线虫C.对挥发性麻醉剂非常敏感。我们现在已经证明复合物I活性与C.优雅的人进行广泛的活动。在患有线粒体疾病的儿童中，已发表的报告引用了在麻醉剂暴露期间和之后发生的严重的，无法解释的并发症。我们现在已经麻醉了35名来手术室诊断或治疗假定线粒体疾病的儿童。鉴于报告的不良后果的儿童线粒体细胞病变后，麻醉剂暴露，我们诱导这些儿童非常缓慢地与单一的挥发性麻醉剂。其中7名儿童对七氟烷非常过敏。所有7名过敏儿童都有与线粒体复合物I功能下降一致的缺陷。这是第一次报告的一个特定的生理缺陷，可以深刻地改变麻醉剂的敏感性在人类。我们假设，线粒体缺陷的儿童特异性复合物I是挥发性麻醉药过敏，他们可能会在更大的风险，基于这种超敏反应的不良后果。本研究的具体目的是：1）前瞻性确定线粒体缺陷儿童对挥发性麻醉剂七氟烷的敏感性，并将敏感性与基础线粒体疾病相关联; 2）确定七氟烷用于线粒体疾病儿童的相对安全性。这些转化研究对患者安全以及理解挥发性麻醉剂的作用机制具有重要意义。.